EP1369417A1 - Acridine derivatives - Google Patents

Abstract

Aminomethyl-acridine derivatives (I) are new. Aryl substituted aminomethyl-acridine derivatives of formula (I) and their salts are new. X = N and Y = C; or X = C and Y = N; R1 = A; R2 = H or OR12; R3 = H; or R2 and R3 together form a double bond; R4 = CH2NR14R15; R5 and R6 = H or 1-6C alkyl; and R7 and R8 = H; or R3 = A; R1, R2, R4, R5, R7 and R8 = H; R4 = OR12; or R1 and R4 together or R4 and R5 together form a double bond; and R6 = CH2NR4R15; or R5 = A; R1-R4 and R7 = H; R6 = H or R12; or R3 and R6 together or R6 and R7 together form a double bond; and R8 = CH2NR14R15; A = group of formula (a); R9 and R10 = H, OH, 1-6C alkoxy, Cl, F, CF3, CN, COOH, CONR17R18, or COOR16; R11 = H, OH, 1-6C alkoxy, 3-7C cycloalkyloxy, aryloxy, or heterocyclyloxy; R12 = H, 1-6C alkyl, aryl, or COR13; R13 and R16 - R18 = 1-6C alkyl or aryl; and R14 and R15 = 1-6C alkyl, aryl or 3-7C cycloalkyl. An Independent claim is also included for the preparation of compounds (I) excluding those where R1 = A, R2 = H or OR12 and R3 = H or R2 and R3 together form a double bond, R4 = CH2NR14R15, R5 and R6 = 1-6C alkyl and R7 and R8 = H.

Description

oder pharmazeutisch verwendbare Salze davon, sowie Verfahren zu ihrer Herstellung und deren Verwendung als Arzneimittel.The invention relates to acridine derivatives of the general formula I

or pharmaceutically acceptable salts thereof, as well as processes for their preparation and their use as medicaments.

Classic opioids such as morphine are effective in the treatment of severe to severe pain. their use However, due to the known side effects z. As respiratory depression, vomiting, sedation, constipation and Tolerance development limited. In addition, they are in neuropathic or incidental pain, among which in particular Tumor patients suffer less effectively.

Opioids exert their analgesic effect by binding to membrane-bound receptors belonging to the family of so-called G protein-coupled receptors. The biochemical and pharmacological characterization of subtypes of these receptors shows that subtype-specific opioids have a different action / side effect profile than, for example, Morphine. While morphine binds selectively to the so-called μ-receptors, endogenous enkephalins have been characterized as δ-selective peptides. Further pharmacological investigations have in the meantime made the existence of several subtypes of these opioid receptors (μ ₁ , μ ₂ , κ ₁ , κ ₂ , κ ₃ δ ₁ and δ ₂ ) probable.

Knowledge of the physiological significance of δ receptor-selective substances has been substantially extended by the development of the non-peptidic antagonist naltrindole. It is now established that δ agonists have an independent antinociceptive potential. In addition to a variety of animal studies, there is also a study with the peptide agonist D-alanine ² -D-leucine ⁵ -enkephalin (DADL) in cancer patients, in which morphine had no analgesic effect. When administered intrathecally, DADL showed a long lasting analgesic effect. In addition, δ- of μ agonists differ in their interaction with the "endogenous opioid antagonist" cholecystokinin (CCK).

The problem underlying the invention was to find analgesic substances that show an affinity for δ-opiate receptors.

With the acridine derivatives of the present invention, these requirements have been met. The new compounds show marked δ-opiate receptor affinity.

worin

R¹

A, wenn

R²

H, OR¹² oder R² und R³ zusammen eine Doppelbindung bilden;

R³

H oder R³ und R² zusammen eine Doppelbindung bilden;

R⁴

CH₂NR¹⁴R¹⁵;

R⁵

H, C_1-6-Alkyl;

R⁶

H, C_1-6-Alkyl;

R⁷

H;

R⁸

H;
oder

R³

A, wenn

R¹

H oder R¹ und R⁴ zusammen eine Doppelbindung bilden;

R²

H;

R⁴

H, OR¹² oder R⁴ und R¹ zusammen eine Doppelbindung oder R⁴ und R⁵ zusammen eine Doppelbindung bilden;

R⁵

H oder R⁵ und R⁴ zusammen eine Doppelbindung bilden;

R⁶

CH₂NR¹⁴R¹⁵;

R⁷

H;

R⁸

H;
oder

R⁵

A, wenn

R¹

H;

R²

H;

R³

H oder R³ und R⁶ zusammen eine Doppelbindung bilden;

R⁴

H;

R⁶

H, OR¹² oder R⁶ und R³ zusammen eine Doppelbindung oder R⁶ und R⁷ zusammen eine Doppelbindung bilden;

R⁷

H oder R⁷ und R⁶ zusammen eine Doppelbindung bilden;

R⁸

CH₂NR¹⁴R¹⁵;
und

A

R⁹, R¹⁰

gleich oder verschieden voneinander H, OH, C_1-6-Alkoxy, CI, F, CN, CF₃, COOH, CONR¹⁷R¹⁸, COOR¹⁶;

R¹¹

H, OH, C_1-6-Alkoxy, O-C_3-7-Cycloalkyl, O-Aryl, O-Heterocyclyl;

R¹²

H, C_1-6-Alkyl, Aryl, COR¹³;

R¹³

C_1-6-Alkyl, Aryl;

R¹⁴, R¹⁵

gleich oder verschieden voneinander C_1-6-Alkyl, Aryl, C_3-7-Cycloalkyl;

R¹⁶

C_1-6-Alkyl, Aryl;

R¹⁷, R¹⁸

gleich oder verschieden voneinander C_1-6-Alkyl, Aryl, und
X gleich N wenn Y gleich C, oder X gleich C wenn Y gleich N
bedeuten, oder pharmazeutisch verwendbare Salze davon.

The invention relates to acridine derivatives of the general formula I

wherein

R ¹

A, if

R ²

H, OR ¹² or R ² and R ³ together form a double bond;

R ³

H or R ³ and R ² together form a double bond;

R ⁴

CH ₂ NR ¹⁴ R ^15;

R ⁵

H, C _1-6 alkyl;

R ⁶

H, C _1-6 alkyl;

R ⁷

H;

R ⁸

H;
or

R ³

A, if

R ¹

H or R ¹ and R ⁴ together form a double bond;

R ²

H;

R ⁴

H, OR ¹² or R ⁴ and R ¹ together form a double bond or R ⁴ and R ⁵ together form a double bond;

R ⁵

H or R ⁵ and R ⁴ together form a double bond;

R ⁶

CH ₂ NR ¹⁴ R ^15;

R ⁷

H;

R ⁸

H;
or

R ⁵

A, if

R ¹

H;

R ²

H;

R ³

H or R ³ and R ⁶ together form a double bond;

R ⁴

H;

R ⁶

H, OR ¹² or R ⁶ and R ³ together form a double bond or R ⁶ and R ⁷ together form a double bond;

R ⁷

H or R ⁷ and R ⁶ together form a double bond;

R ⁸

CH ₂ NR ¹⁴ R ^15;
and

A

R ⁹ , R ¹⁰

the same or different H, OH, C _1-6 alkoxy, CI, F, CN, CF ₃ , COOH, CONR ¹⁷ R ¹⁸ , COOR ¹⁶ ;

R ¹¹

H, OH, C _1-6 alkoxy, OC _3-7 cycloalkyl, O-aryl, O-heterocyclyl;

R ¹²

H, C _1-6 alkyl, aryl, COR ¹³ ;

R ¹³

C _1-6 alkyl, aryl;

R ¹⁴ , R ¹⁵

C _1-6 alkyl, aryl, C _3-7 cycloalkyl;

R ¹⁶

C _1-6 alkyl, aryl;

R ^17, R ¹⁸

the same or different from each other C _1-6 alkyl, aryl, and
X equals N if Y equals C, or X equals C if Y equals N
mean, or pharmaceutically acceptable salts thereof.

Preference is given to compounds of the general formula I in which R ¹⁴ , R ^{15 are} identical or different and are C _1-6 -alkyl and R ¹ to R ¹³ , R ¹⁶ to R ¹⁸ , X and Y have the above meaning or
R ¹¹ is OH or C _1-6 alkoxy and R ¹ to R ^10, R ¹² to R ^18, X and Y have the above meaning, or
R ¹ A, R ¹¹ OH or C _1-6 -alkoxy, R ¹⁴ and R ^{15 are the} same or different from each other C _1-6 -alkyl and R ² to R ¹⁰ , R ¹² , R ¹³ , R ¹⁶ to R ¹⁸ , X and Y is the above meaning or
R ³ A, R ¹¹ OH or C _1-6 -alkoxy, R ¹⁴ and R ^{15 are the} same or different from each other C _1-6 -alkyl and R ¹ , R ² , R ⁴ to R ¹⁰ , R ¹² , R ¹³ , R ¹⁶ to R ¹⁸ , X and Y have the above meaning or
R ⁵ A, R ¹¹ OH or C _1-6 -alkoxy, R ¹⁴ and R ^{15 are the} same or different from each other C _1-6 -alkyl and R ¹ to R ⁴ , R ⁶ to R ¹⁰ , R ¹² , R ¹³ , R ¹⁶ to R ¹⁸ , X and Y have the above meaning.

rac-cis-[3-Dimethylaminomethyl-2-(3-methoxy-phenyl)]-1,2,3,4-tetrahydro-acridin-2-ol, Hydrochlorid,

rac-cis-[4-Dimethylaminomethyl-3-(3-methoxy-phenyl)]-1,2,3,4-tetrahydro-acridin-3-ol, Hydrochlorid,

[3-Dimethylaminomethyl-2-(3-hydroxy-phenyl)]-3,4-dihydroacridin-1-en, Hydrochlorid,

rac-trans-[3-Dimethylaminomethyl-2-(3-methoxy-phenyl)]-1,2,3,4-tetrahydro-acridin-2-ol, Hydrochlorid,

rac-cis-[3-Dimethylaminomethyl-2-(3-hydroxy-phenyl)]-1,2,3,4-tetrahydro-acridin-2-ol, Hydrochlorid,

[1-(3-Methoxy-phenyl)-3,4-dihydro-acridin-2-yl-methyl]-dimethylamin, Hydrochlorid,

[3-(3-Methoxy-phenyl)-1,2-dihydro-acridin-2-yl-methyl]-dimethylamin, Hydrochlorid,

[3-Dimethylaminomethyl-2-(3-methoxy-phenyl)]-3,4-dihydroacridin-1-en, Hydrochlorid,

rac-trans-[1-(3-Methoxy-phenyl)-1,2,3,4-tetrahydro-acridin-2-yl-methyl]-dimethylamin, Hydrochlorid,

rac-cis-[1-(3-Methoxy-phenyl)-1,2,3,4-tetrahydro-acridin-2-yl-methyl]-dimethylamin, Hydrochlorid,

rac-trans-[3-(3-Methoxy-phenyl)-1,2,3,4-tetrahydro-acridin-2-yl-methyl]-dimethylamin, Hydrochlorid,

rac-cis-[3-(3-Methoxy-phenyl)-1,2,3,4-tetrahydro-acridin-2-yl-methyl]-dimethylamin, Hydrochlorid,

[3-(2-Dimethylaminomethyl-3,4-dihydro-acridin-1-yl)]-phenol, Hydrochlorid,

[3-(2-Dimethylaminomethyl-1,2-dihydro-acridin-3-yl]-phenol,

rac-trans-[3-(2-Dimethylaminomethyl-1,2,3,4-tetrahydroacridin-3-yl)]-phenol,

rac-trans-[3-(2-Dimethylaminomethyl-1,2,3,4-tetrahydroacridin-1-yl)]-phenol, Hydrochlorid,

rac-cis-[2-Dimethylaminomethyl-1-(3-methoxy-phenyl)]-3,3-dimethyl-1,2,3,4-tetrahydro-acridin-1-ol, Hydrochlorid,

3-(2-Dimethylaminomethyl-3,3-dimethyl-3,4-dihydroacri-din-1-yl)-phenol, Hydrochlorid.

Other preferred compounds include:

rac -cis- [3-dimethylaminomethyl-2- (3-methoxyphenyl)] - 1,2,3,4-tetrahydro-acridin-2-ol, hydrochloride,

rac -cis- [4-dimethylaminomethyl-3- (3-methoxyphenyl)] - 1,2,3,4-tetrahydro-acridin-3-ol, hydrochloride,

[3-dimethylaminomethyl-2- (3-hydroxyphenyl)] - 3,4-dihydroacridin-1-ene, hydrochloride,

rac -trans- [3-dimethylaminomethyl-2- (3-methoxyphenyl)] - 1,2,3,4-tetrahydro-acridin-2-ol, hydrochloride,

rac -cis- [3-dimethylaminomethyl-2- (3-hydroxyphenyl)] - 1,2,3,4-tetrahydro-acridin-2-ol, hydrochloride,

[1- (3-methoxy-phenyl) -3,4-dihydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride,

[3- (3-methoxy-phenyl) -1,2-dihydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride,

[3-dimethylaminomethyl-2- (3-methoxyphenyl)] - 3,4-dihydroacridin-1-ene, hydrochloride,

rac -trans- [1- (3-methoxy-phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride,

rac -cis- [1- (3-methoxy-phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride,

rac -trans- [3- (3-methoxy-phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride,

rac -cis- [3- (3-methoxy-phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine hydrochloride,

[3- (2-dimethylaminomethyl-3,4-dihydro-acridin-1-yl)] -phenol, hydrochloride,

[3- (2-dimethylaminomethyl-1,2-dihydro-acridin-3-yl] -phenol,

rac -trans- [3- (2-dimethylaminomethyl-1,2,3,4-tetrahydroacridin-3-yl)] phenol,

rac -trans- [3- (2-dimethylaminomethyl-1,2,3,4-tetrahydroacridin-1-yl)] phenol, hydrochloride,

rac -cis- [2-dimethylaminomethyl-1- (3-methoxyphenyl)] - 3,3-dimethyl-1,2,3,4-tetrahydro-acridin-1-ol, hydrochloride,

3- (2-dimethylaminomethyl-3,3-dimethyl-3,4-dihydro-atriazin-1-yl) -phenol, hydrochloride.

The term "C _1-6 -alkyl" in the context of the present invention means straight-chain or branched hydrocarbons having 1 to 6 carbon atoms. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, n-butane, sec-butyl, tert-butyl, neopentyl and n-hexane.

The term "C _1-6 -alkoxy" in the context of the present invention means straight-chain or branched hydrocarbons having 1 to 6 carbon atoms as defined above, which are bonded via the oxygen atom.

The expression "C _3-7 -cycloalkyl" in the context of the present invention means saturated cyclic hydrocarbons having 3 to 7 carbon atoms, examples being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term "aryl" in the context of the present invention means unsubstituted or mono- or polysubstituted by OH, F, Cl, CF ₃ , C _1-6 -alkyl, C _1-6 -alkoxy, C _3-7 -cycloalkyl, C _{2 -6-} alkylene, heterocyclyl or phenyl-substituted phenyls. The term may also mean naphthyl.

The term "heterocyclyl" in the context of the present invention means 5- or 6-membered saturated or unsaturated, optionally provided with a fused aryl system, heterocyclic compounds, containing one or two heteroatoms from the group of nitrogen, oxygen and / or sulfur.

Examples of saturated heterocyclyls are pyrrolidine, pyran, thiolane, piperidine or tetrahydrofuran listed.

In the group of unsaturated heterocyclyls are, for example, furan, thiophene, pyrrole, pyridine, pyrimidine, Quinoline, isoquinoline, phthalazine or quinazoline.

These compounds are used as analgesics and, more generally, for all pathological conditions can usually be treated with δ-opiate receptors used.

worin R¹⁹, R²⁰ und R²¹ unabhängig voneinander H, C_1-6-Al-koxy, O-C_3-7-Cycloalkyl, O-Aryl oder O-Heterocyclyl darstellen, sowie R¹⁴ und R¹⁵ die gleiche Bedeutung wie oben besitzen, mit substituierten 2-Aminobenzaldehyden umgesetzt. Diese Reaktionen werden in einem C_1-4-Alkylalkohol in Gegenwart einer Säure aus der Gruppe vorzugsweise von Salzsäure, Phosphorsäure oder Schwefelsäure bei Temperaturen zwischen 20° C und 80° C durchgeführt.Furthermore, processes for the preparation of a compound of the formula I are the subject of the invention. For the preparation of the compounds of formula I, wherein derivatives are excluded in which the radicals R ¹ A, R ² H, OR ¹² or R ² and R ³ together form a double bond, R ^{3 is} H or R ³ and R ² together Form double bond, R ⁴ CH ₂ NR ¹⁴ R ¹⁵ , R ⁵ and R ⁶ C _1-6 alkyl, R ⁷ and R ⁸ H, the radicals R ¹¹ , R ¹² , R ¹⁴ and R ^{15 have} the same meaning as above , cyclohexane derivatives of the formula II, III or IV,

wherein R ¹⁹ , R ²⁰ and R ^{21 are} independently H, C _1-6 alkoxy, OC _3-7 cycloalkyl, O-aryl or O-heterocyclyl, and R ¹⁴ and R ^{15 have} the same meaning as above , reacted with substituted 2-Aminobenzaldehyden. These reactions are carried out in a C _1-4 alkyl alcohol in the presence of an acid from the group preferably of hydrochloric, phosphoric or sulfuric acid at temperatures between 20 ° C and 80 ° C.

The elimination of the tertiary OH group and / or cleavage of the methyl ether grouping in the obtained Cyclization products is prepared by reacting the products with an acid from the group preferably formic acid, Acetic acid, hydrobromic acid / glacial acetic acid, hydrobromic acid or methanesulfonic acid / methionine Temperatures between 15 ° C and 80 ° C performed.

The introduction of the radical R ¹² with R ¹² equal to hydrogen is achieved by reaction of the corresponding cyclisation products with the relevant alkyl or aryl halides or the acid chlorides in question in the presence of a base such as potassium carbonate or sodium hydride in an organic solvent. B. dimethylformamide.

The synthesis of the cyclohexanones of the formula II where R ¹⁴ and R ^{15 are the} same as a methyl group has already been described in DE-A 195 47 766.

anschließender Reaktion der so erhaltenen Mannich-Basen mit einer metallorganischen Verbindung der Formel VI,

in der Z MgCl, MgBr, Mgl oder Lithium bedeutet und R²² die Bedeutung gemäß R¹¹ hat und anschließender Abspaltung der Ketalschutzgruppe mit einer Säure, beispielhaft sei Salzsäure genannt, darstellen.Cyclohexanones of the formula II where R ¹⁴ and R ^{15 are} not identical to a methyl group and have the same meaning as described above can be obtained by reacting a 1,4-cyclohexanedione monoethylene ketal with immonium salts of the formula V,

subsequent reaction of the resulting Mannich bases with an organometallic compound of the formula VI,

in which Z denotes MgCl, MgBr, Mgl or lithium and R ^{22 has} the meaning according to R ¹¹ and subsequent cleavage of the ketal protecting group with an acid, which may be mentioned by way of example as hydrochloric acid.

The reaction of the Mannich bases with a Grignard compound of the formula VI in the Z for MgCl, MgBr or Mgl stands, or with an organolithium compound of the formula VI can in an aliphatic ether, for example Diethyl ether and / or tetrahydrofuran be carried out at temperatures between -70 ° C and 60 ° C. The Reaction with a Grignard compound of the formula VI can be carried out with or without the addition of a carry-along reagent, preferably 1,2-dibromoethane take place. Lithium-organic compounds of the formula VI, in which Z is Cl, Br or I, leave obtained by reaction, for example, with n-butyllithium / hexane solution by halogen-lithium exchange.

The cleavage of the methyl ether grouping in the cyclohexane derivatives thus obtained is carried out by reaction the compounds with an acid, for example, formic acid, acetic acid. Hydrobromic acid / glacial acetic acid, hydrobromic acid, Methanesulfonic acid / methionine carried out at temperatures between 15 ° C and 80 ° C.

lassen sich durch Reaktion der Mannich-Base der Formel VII,

in der R¹⁴ und R¹⁵, die gleiche Bedeutung wie oben haben, mit einer metallorganischen Verbindung der Formel VI, in der Z MgCl, MgBr, Mgl oder Lithium bedeuten und R²² die Bedeutung gemäß R¹¹ hat, darstellen.Cyclohexane derivatives of the formula III

can be prepared by reaction of the Mannich base of the formula VII,

in which R ¹⁴ and R ^{15 have} the same meaning as above, with an organometallic compound of the formula VI in which Z is MgCl, MgBr, Mgl or lithium and R ^{22 has} the meaning according to R ¹¹ represent.

The reaction of the Mannich base of the formula VII with a Grignard compound of the formula VI in the Z MgCl, MgBr or MgI, or with an organolithium compound of the formula VI may be in an aliphatic Ether, for example, diethyl ether and / or tetrahydrofuran carried out at temperatures between -70 ° C and 60 ° C. become. The reaction with a Grignard compound of the formula VI can be carried out with or without the addition of a carry-along reagent, preferably 1,2-dibromoethane. Organolithium compounds of VI in which Z is Cl, Br or I, can be obtained by reaction with, for example, n-butyl lithium / hexane solution by halogen-lithium exchange.

The cleavage of the methyl ether group in the cyclohexane derivatives thus obtained is carried out by reacting the compounds with an acid such as formic acid, acetic acid, hydrobromic acid / glacial acetic acid, hydrobromic acid, methanesulfonic acid / methionine at temperatures between 15 ° C and 80 ° C. Mannich bases of the formula VII with R ¹⁴ and R ¹⁵ equal to one methyl group are already described in DE-A 195 25 137. Mannich bases of the formula VII with R ¹⁴ and R ¹⁵ other than a methyl group are obtained by reacting 3,3-dimethyl-1,5-dioxa-spiro [5.5] undecan-8-one with immonium salts of the formula V.

erhält man durch Umsetzung von Cyclohexan-Derivaten der Formel III mit Säuren beispielsweise Salzsäure, Ameisensäure, Essigsäure. Anschließende Hydrierung der so erhaltenen Produkte mit katalytisch aktiviertem Wasserstoff, wobei Platin oder Palladium, absorbiert auf einem Trägermaterial wie Aktivkohle, als Katalysator dienen, führt zu Verbindungen der Formel IV. Die Hydrierung wird in einem Lösemittel wie Essigsäureethylester oder einem C_1-4-Alkylalkohol bei Drücken von 0,1 bis 10 bar und Temperaturen von 20° C bis 80° C durchgeführt. Die Spaltung der Methylethergruppe in Verbindungen der Formel IV gelingt durch Umsetzung mit Bromwasserstoffsäure, Bromwasserstoffsäure/Eisessig bei Temperaturen zwischen 20° C und 80° C.Cyclohexanones of the formula IV

is obtained by reacting cyclohexane derivatives of the formula III with acids, for example hydrochloric acid, formic acid, acetic acid. Subsequent hydrogenation of the products thus obtained with catalytically activated hydrogen, wherein platinum or palladium absorbed on a support material such as activated carbon, are used as a catalyst, leads to compounds of formula IV. The hydrogenation is carried out in a solvent such as ethyl acetate or a C _1-4 alkyl alcohol at pressures of 0.1 to 10 bar and temperatures of 20 ° C to 80 ° C carried out. The cleavage of the methyl ether group in compounds of formula IV is possible by reaction with hydrobromic acid, hydrobromic acid / glacial acetic acid at temperatures between 20 ° C and 80 ° C.

Acridine derivatives of general formula I, for which R ¹ A, R ^{2 is} H, OR ¹² or R ² and R ^{3 is} part of a double bond, R ^{3 is} H or R ³ and R ^{2 is} part of a double bond, R ^{4 is} CH ₂ NR ¹⁴ R ¹⁵ , R ⁵ and R ⁶ C _1-6 alkyl, R ⁷ and R ⁸ H, wherein the radicals R ¹¹ , R ¹² , R ¹⁴ and R ^{15 have} the same meaning as above, can be preferably by reaction of 3 , 3-dialkyl-3,4-dihydro-2H-acridin-1-one derivatives [cf. Borsche et al., Justus Liebigs Ann. Chem. 550 , 160, (1942)] with immonium chlorides of the formula V at temperatures between 20 ° C and 80 ° C in a solvent such as acetonitrile. The resulting Mannich bases are reacted with an organometallic compound of the formula VI in an aliphatic ether z. B. diethyl ether and / or tetrahydrofuran at temperatures between -70 ° C and + 60 ° C. The elimination of the tertiary OH group and / or the cleavage of the methyl ether group in the products thus obtained can with acid z. For example, formic acid, acetic acid, bromwasserstoffsäure / glacial acetic acid, hydrobromic acid, methanesulfonic acid / methionine at temperatures between 20 ° C and 100 ° C are performed. By hydrogenating the aliphatic double bond in these products with catalytically activated hydrogen, wherein platinum or palladium absorbed on a support material, for. As activated carbon, serve as a catalyst, the compounds of the formula I according to the invention are obtained wherein R ¹ A, R ² H, R ³ H, R ⁴ (CH ₂ ) N (CH ₃ ) ₂ , R ⁵ CH ₃ , R ⁶ CH ₃ , R ⁷ and R ^{8 are} H. The reaction is carried out in a solvent such as acetic acid, ethyl acetate or a C _1-4 -alkyl alcohol at pressures of 0.1 to 10 bar and temperatures of 20 ° C to 80 ° C.

The introduction of the radical R ¹² with R ¹² other than hydrogen is possible by reacting the corresponding cyclization with the relevant alkyl, aryl halides or acid chlorides in the presence of a base such as potassium tertiary butylate, sodium hydride in an organic solvent preferably dimethylformamide.

The compounds of the formula I can be reacted with physiologically tolerated acids such as hydrochloric acid, hydrobromic acid, Sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, Mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and / or aspartic acid in per se known Into its salts. Preferably, salt formation in a solvent such as diisopropyl ether, alkyl acetate, Acetone and / or 2-butanone. For the preparation of the hydrochlorides trimethylchlorosilane is in water Solution particularly suitable.

δ-opiate receptor binding studies

The investigations for determining the affinity of the compounds of the formula I according to the invention for the δ-opiate receptor was to brain membrane homogenates (homogenate of rat brain without cerebellum and medulla oblongata of male Wistar rats).

For this purpose, freshly prepared rat brains were homogenised under ice-cooling in 50 mmol / l Tris-HCl (pH 7.4) and centrifuged for 10 minutes at 5,000 g and 4 ° C. After decanting and discarding the supernatant, re-taking up and homogenizing the membrane sediment in 50 mmol / l Tris-HCl (pH 7.4), the homogenate was then centrifuged for 20 minutes at 20,000 g and 4 ° C. This washing step was repeated again. Thereafter, the supernatant was decanted and the membrane sediment was homogenized in cold 50 mmol / l Tris-HCl, 20% glycerol (w / v), 0.01% bacitracin (w / v) (pH 7.4) and in aliquots until tested frozen. For the receptor binding assay, the aliquots were thawed and diluted 1:10 with the binding assay buffer. In the binding test, the buffer used was a 50 μmol / l Tris-HCl, 5 μmol / l MgCl ₂ (pH 7.4) supplemented with 0.1% (w / v) bovine serum albumin, and as radioactive ligand 1 nmol / l [ ³ H ] -2-D-Ala-Deltorphin II used. The proportion of non-specific binding was determined in the presence of 10 .mu.mol / l naloxone.

In further batches, the compounds according to the invention were added in concentration stages and determined the displacement of the radioactive ligand from its specific binding. The respective triple approaches were incubated for 90 minutes at 37 ° C and then to determine the bound to the membrane homogenate radioactive ligands were harvested by filtration through glass fiber filters (GF / B). The glass fiber filter discs were dried and measured their radioactivity after addition of scintillator in β-counter.

The affinity of the compounds according to the invention for the δ-opiate receptor was calculated as IC ₅₀ according to the law of mass action by means of nonlinear regression. From the IC ₅₀ values, K _i values were calculated according to the Cheng-Prussoff equation. The K _i values in Table 1 are given as mean ± standard deviations from 3 independent experiments. connection δ-Opiatrezeptorbindung
Ki (nM / l) [1- (3-Methoxy-phenyl) -3,4-dihydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride 133 nM ± 15 nM rac -trans- [1- (3-methoxy-phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride 127 nM ± 12 nM [3- (2-Dimethyl-amino-methyl-3,4-dihydro-acridin-1-yl)] -phenol, hydrochloride 3.84 nM ± 1.59 nM rac -trans- [3- (2-dimethylaminomethyl-1,2,3,4-tetrahydro-acridin-1-yl)] - phenol, hydrochloride 4.17 nM ± 0.99 nM rac -cis- [2-dimethylaminomethyl-1- (3-methoxyphenyl)] - 3,3-dimethyl-1,2,3,4-tetrahydroacridin-1-ol, hydrochloride 60.2 nM ± 14.2 nM 3- (2-Dimethylaminomethyl-3,3-dimethyl-3,4-dihydro-acridin-1-yl) -phenol, hydrochloride 29.0 nM ± 3.4 nM

Examples

The yields of the compounds produced are not optimized.

All temperatures are uncorrected.

Silica gel 60 (0.040-0.063 mm) from E. was used as the stationary phase for the column chromatography. Merck, Darmstadt.

The thin-layer chromatographic investigations were carried out with HPTLC precast plates, Kieselgel 60 F 254, from E. Merck, Darmstadt.

The mixing ratios of the eluents for all chromatographic investigations are always in volume / volume specified.

RT means room temperature; Mixture means melting point, the term ether means diethyl ether.

Unless otherwise stated, petroleum ether was used with the boiling range of 50 ° C - 70 ° C.

example 1 rac -cis- [3-dimethylaminomethyl-2- (3-methoxyphenyl)] - 1,2,3,4-tetrahydro-acridin-2-ol, hydrochloride and rac -cis- [4-dimethylaminomethyl-3- (3 -methoxy-phenyl)] - 1,2,3,4-tetrahydro-acridin-3-ol, hydrochloride

4.8 g rac -cis- [3-dimethylaminomethyl-4-hydroxy-4- (3-methoxy-phenyl)] - cyclohexanone and 6.0 g 2-aminobenzaldehyde as the hydrochloride were at 20 ° C under nitrogen in 200 ml methanol solved. Subsequently, the reaction mixture was heated to 80 ° C and added at this temperature with 20 ml of 1 N hydrochloric acid. After a further 48 hours, the reaction solution was cooled to 0 ° C, treated with 200 ml of ethyl acetate and alkalized with saturated sodium hydroxide solution. The aqueous phase was extracted three times with 100 ml of ethyl acetate, the combined organic phases were dried over magnesium sulfate and the mixture was concentrated in vacuo. The residue was purified by column chromatography with ethyl acetate / methanol in the ratio 4/1 as eluent. The first fraction contained 1.2 g of rac -cis- [4-dimethylaminomethyl-3- (3-methoxyphenyl)] - 1,2,3,4-tetrahydroacridin-3-ol base as an amorphous beige solid. To prepare the hydrochloride, the solid was dissolved with heating in 50 ml of acetone and treated with an equimolar amount of trimethylchlorosilane and water. There was added 1.0 g of rac -cis- [4-dimethylaminomethyl-3- (3-methoxyphenyl)] - 1,2,3,4-tetrahydro-acridin-3-ol, hydrochloride (32% of theory). ) in the form of white crystals; M .: 175 ° C to 180 ° C

The second fraction also yielded 2.0 g of rac -cis- (3-dimethylaminomethyl-2- (3-methoxyphenyl)] - 1,2,3,4-tetrahydroacridin-2-ol base as an amorphous beige solid Reaction of the solid with an equimolar amount of trimethylchlorosilane and water in 200 ml of acetone gave 1.9 g (61.3% of theory) of rac -cis- [3-dimethylaminomethyl-2- (3-methoxyphenyl)] - 1,2,3,4-tetrahydro-acridin-2-ol, hydrochloride in the form of white crystals (mp: 181 ° C to 183 ° C).

Example 2 rac -trans- [3-dimethylaminomethyl-2- (3-methoxyphenyl)] - 1,2,3,4-tetrahydro-acridin-2-ol, hydrochloride and rac -cis- [3-dimethylaminomethyl-2- ( 3-hydroxy-phenyl)] - 1,2,3,4-tetrahydro-acridin-2-ol, hydrochloride

rac-trans-[3-Dimethylaminomethyl-4-hydroxy-4-(3-methoxyphenyl)]-cyclohexanon und rac-cis-[3-Dimethylaminomethyl-4-hydroxy-4-(3-hydroxyphenyl)]-cyclohexanon

anstelle von rac-cis-[3-Dimethylaminomethyl-4-hydroxy-4-(3-methoxy-phenyl)]-cyclohexanon in Beispiel 1 erhielt man unter Verwendung der in Beispiel 1 beschriebenen Verfahrensweise:

rac -trans-[3-Dimethylaminomethyl-2-(3-methoxy-phenyl)]-1,2,3,4-tetrahydro-acridin-2-ol, Hydrochlorid (Schmp.: 186° C - 190° C).

rac -cis-[3-Dimethylaminomethyl-2-(3-hydroxy-phenyl)]-1,2,3,4-tetrahydro-acridin-2-ol, Hydrochlorid (Schmp.: > 250° C)

Eine rac-cis-[4-Dimethylaminomethyl-3-(3-methoxy-phenyl)]-1,2,3,4-tetrahydro-acridin-3-ol Hydrochlorid analoge Verbindung wurde in beiden Fällen nicht erhalten.

Using the cyclohexanones:

rac -trans- [3-dimethylaminomethyl-4-hydroxy-4- (3-methoxyphenyl)] - cyclohexanone and rac -cis- [3-dimethylaminomethyl-4-hydroxy-4- (3-hydroxyphenyl)] - cyclohexanone

instead of rac -cis- [3-dimethylaminomethyl-4-hydroxy-4- (3-methoxyphenyl)] cyclohexanone in Example 1, the procedure described in Example 1 was followed.

rac -trans- [3-dimethylaminomethyl-2- (3-methoxyphenyl)] - 1,2,3,4-tetrahydro-acridin-2-ol, hydrochloride (m.p .: 186 ° C - 190 ° C).

rac -cis- [3-dimethylaminomethyl-2- (3-hydroxyphenyl)] - 1,2,3,4-tetrahydro-acridin-2-ol, hydrochloride (mp:> 250 ° C)

A rac -cis- [4-dimethylaminomethyl-3- (3-methoxyphenyl)] - 1,2,3,4-tetrahydro-acridin-3-ol hydrochloride analog was not obtained in either case.

Example 3 [3-Dimethylaminomethyl-2- (3-hydroxyphenyl)] - 3,4-dihydro-acridine-1-ene, hydrochloride and [3-dimethylaminomethyl-2- (3-methoxyphenyl] -3,4-dihydro acridin-1-ene, hydrochloride

3.65 g of rac -cis- [3-dimethylaminomethyl-2- (3-methoxyphenyl)] - 1,2,3,4-tetrahydro-acridin-2-ol base were washed at RT with 20 ml of methanesulfonic acid and 2, 2 g methionine added. The reaction mixture was stirred for three days at 20 ° C, the solution was concentrated in vacuo to dryness; the solid was dissolved in water, the solution was covered with ethyl acetate and alkalized with saturated sodium carbonate solution. The aqueous phase was extracted three times with 200 ml of ethyl acetate, the combined organic phases dried over magnesium sulfate and freed from the solvent in vacuo. The residue was purified by column chromatography with ethyl acetate / methanol in the ratio 6/1 as eluent. The first product fraction contained 0.3 g of [3-dimethylaminomethyl-2- (3-methoxy-phenyl)] - 3,4-dihydro-acridine-1-ene base. To prepare the hydrochloride, the amorphous solid was dissolved in 50 ml of acetone and treated with an equimolar amount of trimethylchlorosilane and water. 0.3 g (7.9% of theory) of [3-dimethylaminomethyl-2- (3-methoxyphenyl)] - 3,4-dihydro-acridin-1-ene, hydrochloride in the form of a beige, crystalline solid (mp .: 195 ° C - 197 ° C). The second product fraction yielded 2.2 g of 3-dimethylaminomethyl-2- (3-hydroxyphenyl)-3,4-dihydroacridin-1-ene base, which was prepared by reaction with an equimolar amount of trimethylchlorosilane / water in 2.1 g ( 57.5% of theory) of the title compound [3-dimethylaminomethyl-2- (3-hydroxyphenyl)] - 3,4-dihydroacridin-1-ene, hydrochloride (mp: 200 ° C to 204 ° C) ,

Example 4 [1- (3-Methoxy-phenyl) -3,4-dihydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride and [3- (3-methoxy-phenyl) -1,2-dihydro-acridine-2 yl-methyl] -dimethylamine, hydrochloride Step 1: rac cis- [9-dimethylaminomethyl-8- (3-methoxy-phenyl)] - 3,3-dimethyl-1,5-dioxa-spiro [5.5) undecan-8-ol

36 g of magnesium turnings were suspended with stirring and passing dry nitrogen in 100 ml of absolute tetrahydrofuran. Subsequently, 280 g of m-bromoanisole, dissolved in 200 ml of absolute tetrahydrofuran, were added dropwise at 60.degree. After completion of the bromoanisole addition, the reaction mixture was stirred for a further hour at 60 ° C. Subsequently, at 15 ° C. to 20 ° C., 244 g of 9-dimethylaminomethyl-3,3-dimethyl-1,5-dioxaspiro [5.5] undecane were added. Dissolved 8-on in 1000 ml of absolute tetrahydrofuran and added dropwise. The reaction mixture was stirred overnight with ice-cooling and decomposed with 1000 ml of saturated ammonium chloride solution under ice-cooling. The aqueous phase was extracted twice with 250 ml of ether. The combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the residue was added with petroleum ether until the title compound crystallized out. 150 g (41% of theory) of rac -cis- [9-dimethylaminomethyl-8- (3-methoxyphenyl)] - 3,3-dimethyl-1,5-dioxa-spiro [5.5] undecane-8- ol, in the form of white crystals; Melting point: 91 ° C to 93 ° C.

Level 2: [1- (3-Methoxy-phenyl) -3,4-dihydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride and [3- (3-methoxy-phenyl) -1,2-dihydro-acridine-2 yl-methyl] -dimethylamine, hydrochloride

18 g of the product from step 1 were dissolved under dry nitrogen in 200 ml of methanol. The reaction mixture was added 7.7 g of 2-aminobenzaldehyde hydrochloride and then heated to 80 ° C. Nach Addition of 100 ml of 1N hydrochloric acid stirred the reaction solution for eight days at 80 ° C. After cooling to room temperature diluted with the reaction mixture with 200 ml of ethyl acetate and alkalized with ice cooling with concentrated Sodium hydroxide solution. The aqueous phase was extracted three times with 100 ml of ethyl acetate, The combined organic phases were dried over magnesium sulfate and concentrated in vacuo to dryness. The Residue was eluted and purified by column chromatography on silica gel with ethyl acetate / methanol in the ratio 1.4. The first product fraction contained 5.4 g of [3- (3-methoxy-phenyl) -1,2-dihydro-acridin-2-yl-methyl] -dimethylamine Base in the form of beige crystals. The solid was prepared by heating in 200 ml of acetone to give the hydrochloride dissolved and added with an equimolar amount of trimethylchlorosilane and water. This gave 5.2 g (28.3% of theory) of [3- (3-methoxy-phenyl) -1,2-dihydro-acridin-2-yl-methyl] -dimethylamine, Hydrochloride (pale yellow crystals, mp. 201 ° C up to 204 ° C). The second fraction was 4.4 g of [1- (3-methoxy-phenyl) -3,4-dihydro-acridin-2-yl-methyl] -dimethylamine Base in the form of a beige, amorphous solid. To release the hydrochloride, the solid was dissolved Heat in 200 ml of acetone and add with an equimolar amount of trimethylchlorosilane and water. One received 4.2 g (22.90% of theory) of [1- (3-methoxy-phenyl) -3,4-dihydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride in the form of pale yellow Crystals, mp .: 195 ° C to 198 ° C.

Example 5 [3- (2-dimethylaminomethyl-3,4-dihydro-acridin-1-yl)] phenol, hydrochloride

5.4 g of [1- (3-methoxy-phenyl) -3,4-dihydro-acridin-2-yl-methyl] -dimethylamine base were added at RT to 40 ml of methanesulfonic acid and 5.4 g of methionine. The reaction mixture was stirred for 10 days at 20 ° C and was in vacuo concentrated to dryness. The solid was dissolved in water and the solution was overlaid with ethyl acetate and alkalized with saturated sodium carbonate solution. The aqueous phase was extracted three times with 200 ml of ethyl acetate, The combined organic phases were dried over magnesium sulphate and concentrated in vacuo up to Dry. 2.4 g of [3- (2-dimethylaminomethyl-3,4-dihydro-acridin-1-yl)] -phenol base were obtained. Solving the yellow, amorphous solid with heating in acetone and equimolar amount of trimethylchlorosilane and Water provided 2.3 g of [3- (2-dimethylaminomethyl-3,4-dihydroacridin-1-yl)] phenol, hydrochloride (48% of theory) in the form of pale yellow crystals. (Mp .:> 250 ° C).

Example 6 3- (2-dimethylaminomethyl-1,2-dihydro-acridin-3-yl] -phenol Using:

[3- (3-methoxy-phenyl) -1,2-dihydro-acridin-2-yl-methyl] -dimethylamine in place of [1- (3-methoxy-phenyl) -3,4-dihydro-acridin-2-yl methyl] -dimethyl-amine, was obtained according to Example 5 using the described there Procedure:

[3- (2-dimethylaminomethyl-1,2-dihydro-acridin-3-yl] -phenol (mp .: 202 ° C-206 ° C)

Example 7 rac trans [1- (3-methoxy-phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride and rac -trans- [3- (3-methoxy-phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride Step 1: [4-dimethylaminomethyl-3- (3-methoxy-phenyl)] - cyclohex-2-en-one

56 g of the product from step 1 according to Example 4 was added with stirring in a nitrogen atmosphere in 370 ml Tetrahydrofuran dissolved. A mixture of 150 ml of concentrated hydrochloric acid and 150 ml of water was added under ice-cooling added dropwise. The reaction mixture was stirred for two days at room temperature, was washed with 200 ml of ethyl acetate diluted and alkalized with saturated sodium hydroxide solution. The aqueous phase was extracted three times with 100 each ml of ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated in vacuo. The remaining oil was in 200 ml Dissolved acetone and treated with an equimolar amount of trimethylchlorosilane and water. 38.3 g of [4-dimethylaminomethyl-3- (3-methoxyphenyl)] - cyclohex-2-enone were obtained as hydrochloride in the form of pale yellow crystals. To release the base, the solid was dissolved in water with ice cooling, covered with ethyl acetate and alkalized with saturated sodium carbonate solution. The aqueous phase was washed three times with 100 ml of ethyl acetate extracted and dried over magnesium sulfate. After evaporation of the solvent in vacuo, 36 g (88.7 % d. Th.) Of the title compound as a yellow oil.

Level 2: rac - [4-dimethylaminomethyl-3- (3-methoxyphenyl)] - cyclohexanone

28.5 g of the product from Step 1 were dissolved in 250 ml of absolute methanol. While stirring and passing dry nitrogen, 2.8 g of palladium-carbon (10%) was added as a catalyst. The mixture was then hydrogenated at a pressure of 0.2 bar and a temperature of 20 ° C for five hours. After filtration, the solvent was evaporated in vacuo and the residue purified by column chromatography on silica gel with ethyl acetate / methanol / diisopropyl ether in the ratio 4/1/5 as eluent. 7.2 g (25.4% of theory) of rac -cis- [4-dimethylaminomethyl-3- (3-methoxyphenyl)] cyclohexanone as an oil were obtained as the first product fraction. The second product fraction also yielded 7.4 g (26.1% of theory) of rac -trans- [4-dimethylaminomethyl-3- (3-methoxyphenyl)] cyclohexanone as an oil.

Level 3: rac -trans- [1- (3-methoxy-phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride and rac -trans- [3- (3-methoxy- phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride

2.6 g of rac -trans- [4-dimethylaminomethyl-3- (3-methoxyphenyl)] -cyclohexanone were dissolved in 100 ml of ethanol while stirring and passing dry nitrogen over. The reaction mixture was treated with 3.2 g of 2-aminobenzaldehyde hydrochloride and heated to 80 ° C. At this temperature, 11 ml of 1 N hydrochloric acid was added and the reaction solution was stirred at 80 ° C for two days. After cooling to room temperature, the reaction mixture was diluted with 100 ml of ethyl acetate and alkalized under ice-cooling with concentrated sodium hydroxide solution. The aqueous phase was extracted three times with 100 ml of ethyl acetate and the combined organic phases were dried over magnesium sulfate. After removal of the solvent in vacuo, the residue was purified by column chromatography on silica gel with ethyl acetate / methanol in a ratio of 4/1. The first product fraction contained 2.1 g of rac -trans- [3- (3-methoxy-phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine base in the form of beige crystals with an equimolar amount of trimethylchlorosilane / water in 2 g (52.6% of theory) of the title compound rac -trans- [3- (3-methoxy-phenyl) -1,2,3,4-tetrahydro-acridine-2 -yl-methyl] -dimethylamine, hydrochloride (pale yellow crystals, mp: 184 ° C to 187 ° C) were transferred. The second fraction contained 0.4 g of rac -trans- [1- (3-methoxyphenyl) -1,2,3,4-tetrahydroacridin-2-ylmethyl] -dimethylamine base. To release the hydrochloride, the solid was dissolved with heating in 50 ml of acetone, treated with an equimolar amount of trimethylchlorosilane and water. 0.4 g (10.5% of theory) of the hydrochloride rac -trans- [1- (3-methoxyphenyl) -1,2,3,4-tetrahydro-acridin-2-ylmethyl was obtained ] -dimethylamine, hydrochloride, in the form of pale yellow crystals, mp: 167 ° C to 170 ° C.

Example 8 rac -cis- [1- (3-methoxy-phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride and rac -cis- [3- (3-methoxy- phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride

rac-cis-[1-(3-Methoxy-phenyl)-1,2,3,4-tetrahydro-acridin-2-yl-methyl]-dimethylamin

Using:

rac -cis- [1- (3-methoxy-phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine

rac-trans-[3-(3-Methoxy-phenyl)-1,2,3,4-tetrahydro-acridin-2-yl-methyl]-dimethylamin in Beispiel 7 wurde unter Anwendung der in Beispiel 7 beschriebenen Verfahrensweise erhalten:

rac -cis-[1-(3-Methoxy-phenyl)-1,2,3,4-tetrahydro-acridin-2-yl-methyl]-dimethylamin, Hydrochlorid (Schmp.: 118° C - 120° C)

rac -cis-[3-(3-Methoxy-phenyl)-1,2,3,4-tetrahydro-acridin-2-yl-methyl]-dimethylamin, Hydrochlorid (Schmp.: 210°C 213°C)

instead of

rac -trans- [3- (3-methoxy-phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine in Example 7 was obtained using the procedure described in Example 7:

rac -cis- [1- (3-methoxy-phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride (m.p .: 118 ° C - 120 ° C)

rac -cis- [3- (3-methoxy-phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride (mp .: 210 ° C 213 ° C)

Example 9 rac -trans- [3- (2-dimethylaminomethyl-1,2,3,4-tetrahydroacridin-1-yl)] phenol, hydrochloride

1 g of rac -trans- [1- (3-methoxyphenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine base was added at room temperature with 8 ml of methanesulfonic acid and 1 g of methionine , The reaction mixture was stirred for 10 days at 20 ° C, and was then concentrated in vacuo to dryness. The solid was dissolved in water, the solution was coated with ethyl acetate and alkalized with a saturated sodium carbonate solution. The aqueous phase was extracted three times with 200 ml of ethyl acetate, dried the combined organic phases over magnesium sulfate and concentrated in vacuo to dryness. 0.5 g of rac -trans- [3- (2-dimethylaminomethyl-1,2,3,4-tetrahydro-acridin-1-yl)] phenol base was obtained. Dissolution of the yellow, amorphous solid with heating in acetone and equimolar amount of trimethylchlorosilane and water afforded 0.5 g (52% of theory) of rac -trans- [3- (2-dimethyl-aminomethyl-1,2, 3,4-tetrahydro-acridin-1-yl)] phenol hydrochloride (pale yellow crystals, mp: 240 ° C).

Example 10 rac -trans- [3- (2-dimethylaminomethyl-1,2,3,4-tetrahydro-acridin-3-yl)] -phenol

rac-trans-[3-(3-Methoxy-phenyl)-1,2,3,4-tetrahydro-acridin-2-yl-methyl]-dimethylamin anstelle von

rac-trans-[1-(3-Methoxy-phenyl)-1,2,3,4-tetrahydro-acridin-2-yl-methyl]-dimethylamin in Beispiel 9 erhielt man unter Verwendung der in Beispiel 9 beschriebenen Verfahrensweise:

rac -trans-[3-(2-Dimethylaminomethyl-1,2,3,4-tetrahydroacridin-3-yl)]-phenol

Using:

rac -trans- [3- (3-methoxy-phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine instead of

rac -trans- [1- (3-methoxy-phenyl) -1,2,3,4-tetrahydro-acridin-2-yl-methyl] -dimethylamine in Example 9 was obtained using the procedure described in Example 9:

rac -trans- [3- (2-dimethylaminomethyl-1,2,3,4-tetrahydroacridin-3-yl)] - phenol

Example 11 3- (2-dimethylaminomethyl-3,3-dimethyl-3,4-dihydro-acridin-1-yl) -phenol, hydrochloride Step 1: 2-dimethylaminomethyl-3,3-dimethyl-3,4-dihydro-2H-acridin-1-one

A solution of 2.25 g of 3,3-dimethyl-3,4-dihydro-2H-acridin-1-one [W. Borsche et al., Justus Liebigs Ann. Chem. 550 , 160 (1942)] in 12 ml of dry acetonitrile was treated with 0.95 g of N, N-dimethylmethyleneimmonium chloride and one drop of acetyl chloride and the mixture was stirred for 3 days at 20 ° C. It was washed with 30 ml of dist. Water added and extracted twice with ethyl acetate. The aqueous phase was made alkaline by the addition of solid potassium carbonate (pH 9) and extracted three times with dichloromethane. The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness in vacuo. 0.92 g (32.5% of theory) of the title compound in the form of a slightly yellow oil remained.

Level 2: rac -cis- [2-dimethylaminomethyl-1- (3-methoxyphenyl)] - 3,3-dimethyl-1,2,3,4-tetrahydro-acridin-1-ol

A solution of 0.75 g of 3-bromoanisole in 12 ml of dry tetrahydrofuran was stirred at -50 ° C with stirring and Passing dry nitrogen was added dropwise with 2.5 ml of a 1.6 M solution of n-butyllithium in n-hexane. After the end of the addition, stirring was continued for 30 minutes and a solution of 0.85 g of the product was added dropwise from Step 1 in 2 ml dry tetrahydrofuran added. After a reaction time of two hours at -50 ° C was decomposed with 10% hydrochloric acid and extracted twice with ethyl acetate. The hydrochloric acid phase alkalized with potassium carbonate and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography Silica gel with ethyl acetate / methanol in the ratio 9/1 purified as eluent. 0.47 g (40% of theory) were obtained. Th.) Of the title compound as a viscous mass.

level 3 3- (2-dimethylaminomethyl-3,3-dimethyl-3,4-dihydro-acridin-1-yl) -phenol, hydrochloride

A mixture of 0.39 g of the product from Stage 2, 2 ml of methanesulfonic acid and 0.227 g of methionine stirred nine Days at 20 ° C, then another ten days at 40 ° C. Then it was decomposed with ice, alkalized with a saturated Sodium bicarbonate solution and extracted three times with ethyl acetate. The extracts were mixed with a Washed saturated sodium chloride solution, dried over sodium sulfate and largely evaporated in vacuo.

The precipitated upon addition of the residue with n-hexane solid was separated and in vacuo dried. (Yield: 0.26 g). The solid was dissolved by heating in a mixture of 12 ml of acetone, 3.5 ml Tetrahydrofuran and converted with an equimolar amount of trimethylchlorosilane and water in the hydrochloride. you obtained 0.175 g (44.3% of theory) of the title compound in the form of crystals which melted at 240 ° C with decomposition.

Claims (10)

Acridine derivatives of the general formula I,

wherein

R ¹

A, if

R ²

H, OR ¹² or R ² and R ³ together form a double bond,

R ³

H or R ³ and R ² together form a double bond,

R ⁴

CH ₂ NR ¹⁴ R ^15;

R ⁵

H, C _1-6 alkyl;

R ⁶

H, C _1-6 alkyl;

R ⁷

H;

R ⁸

H;
or

R ³

A, if

R ¹

H or R ¹ and R ⁴ together form a double bond;

R ²

H;

R ⁴

H, OR ¹² or R ⁴ and R ¹ together form a double bond or R ⁴ and R ⁵ together form a double bond;

R ⁵

H or R ⁵ and R ⁴ together form a double bond;

R ⁶

CH ₂ NR ¹⁴ R ^15;

R ⁷

H;

R ⁸

H;
or

R ⁵

A, if

R ¹

H;

R ²

H;

R ³

H or R ³ and R ⁶ together form a double bond;

R ⁴

H;

R ⁶

H, OR ¹² or R ⁶ and R ³ together form a double bond, R ⁶ and R ⁷ together form a double bond;

R ⁷

H or R ⁷ and R ⁶ together form a double bond;

R ⁸

CH ₂ NR ¹⁴ R ^15;
and

A

R ⁹ , R ¹⁰

H, OH, C _1-6 -alkoxy, Cl, F, CF ₃ , CN, COOH, CONR ¹⁷ R ¹⁸ , COOR ¹⁶ ;

R ¹¹

H, OH, C _1-6 alkoxy, OC _3-7 cycloalkyl, O-aryl, O-heterocyclyl;

R ¹²

H, C _1-6 alkyl, aryl, COR ¹³

R ¹³

C _1-6 alkyl, aryl,

R ¹⁴ , R ¹⁵

C _1-6 alkyl, aryl, C _3-7 cycloalkyl;

R ¹⁶

C _1-6 alkyl, aryl,

R ^17, R ¹⁸

identical or different from each other C _1-6 alkyl, aryl; and
X equals N if Y equals C, or X equals C if Y equals N
mean, or pharmaceutically acceptable salts thereof.

Compounds according to Claim 1, characterized in that R ¹⁴ and R ^15, equal to or different from each other, denote C _1-6 -alkyl. Compounds according to claim 1, characterized in that R ^{11 is} OH or C _1-6 -alkoxy. Compounds according to Claim 1, characterized in that R ¹ A, R ¹¹ OH or C _1-6 -alkoxy, R ¹⁴ and R ¹⁵ independently of one another are C _1-6 -alkyl. Compounds according to Claim 1, characterized in that R ³ A, R ¹¹ OH or C _1-6 -alkoxy, R ¹⁴ and R ¹⁵ independently of one another are C _1-6 -alkyl. Compounds according to Claim 1, characterized in that R ⁵ A, R ¹¹ OH or C _1-6 -alkoxy, R ¹⁴ and R ¹⁵ independently of one another are C _1-6 -alkyl. Compounds according to claim 1 selected from the group: rac -cis- [3-dimethylaminomethyl-2- (3-methoxyphenyl)] - 1,2,3,4-tetrahydro-acridin-2-ol, hydrochloride; rac -cis- [4-dimethylaminomethyl-3- (3-methoxyphenyl)] - 1,2,3,4-tetrahydro-acridin-3-ol, hydrochloride; [3-dimethylaminomethyl-2- (3-hydroxyphenyl)] - 3,4-dihydro-acridine-1-ene, hydrochloride; rac -trans- [3-dimethylaminomethyl-2- (3-methoxyphenyl)] - 1,2,3,4-tetrahydro-acridin-2-ol, hydrochloride; rac-cis- [3-dimethylaminomethyl-2- (3-hydroxyphenyl)] - 1,2,3,4-tetrahydro-acridin-2-ol, hydrochloride; [1- (3-methoxy-phenyl) -3,4-dihydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride; [3- (3-methoxy-phenyl) -1,2-dihydro-acridin-2-yl-methyl] -dimethylamine, hydrochloride; [3-dimethylaminomethyl-2- (3-methoxyphenyl)] - 3,4-dihydro-acridin-1-ene, hydrochloride; rac -trans- [1- (3-methoxyphenyl) -1,2,3,4-tetrahydroacridin-2-ylmethyl] -dimethylamine, hydrochloride; rac -cis- [1- (3-methoxyphenyl) -1,2,3,4-tetrahydroacridin-2-ylmethyl] -dimethylamine, hydrochloride; rac -trans- [3- (3-methoxyphenyl) -1,2,3,4-tetrahydroacridin-2-ylmethyl] -dimethylamine, hydrochloride; rac -cis- [3- (3-methoxyphenyl) -1,2,3,4-tetrahydroacridin-2-ylmethyl] -dimethylamine, hydrochloride; [3- (2-dimethylaminomethyl-3,4-dihydro-acridin-1-yl)] phenol, hydrochloride; [3- (2-dimethylaminomethyl-1,2-dihydro-acridin-3-yl] -phenol; rac -trans- [3- (2-dimethylaminomethyl-1,2,3,4-tetrahydro-acridin-3-yl)] -phenol; rac -trans- [3- (2-dimethylaminomethyl-1,2,3,4-tetrahydro-acridin-1-yl)] -phenol, hydrochloride; rac -cis- [2-dimethylaminomethyl-1- (3-methoxyphenyl)] - 3,3-dimethyl-1,2,3,4-tetrahydro-acridin-1-ol, hydrochloride; 3- (2-Dimethylaminomethyl-3,3-dimethyl-3,4-dihydro-acridin-1-yl) -phenol, hydrochloride. Process for the preparation of acridine derivatives of the general formula (I)

wherein
R ¹ to R ^{10 have} the meaning of claim 1, wherein derivatives are excluded, in which the radicals have the following meaning that R ¹ A, R ² H, OR ¹² or R ² and R ³ together form a double bond,
R ^{3 is} H or R ³ and R ² together form a double bond, R ^{4 is} CH ₂ NR ¹⁴ R ¹⁵ , R ⁵ and R ^{6 is} C _1-6 -alkyl, R ⁷ and
R ⁸ H, and the radicals R ¹¹ , R ¹² , R ¹⁴ and R ^{15 have} the same meaning as in claim 1, characterized in that cyclohexane derivatives of the general formulas II, III, or IV

wherein
R ¹⁹ , R ²⁰ and R ²¹ independently of one another are H, C _1-6 -alkoxy, O-C _3-7 -cycloalkyl, O-aryl or O-heterocyclyl, and R ¹⁴ and R ^{15 have} the same meaning as in claim 1, be reacted with substituted 2-Aminobenzaldehyden in a solvent from the group of ethyl acetate or of C _1-4 alkyl alcohol in the presence of an acid and the elimination of the tertiary OH group and / or cleavage of the methyl ether group in the resulting cyclization by reaction of the Products with an acid to acridine derivatives of the general formula I is performed. Use of the acridine derivatives of the general formula I according to claim 1 as active ingredient in a medicament. Use according to claim 9, characterized in that the drug is an analgesic.